Skye Bioscience, Inc.

Hello, and thank you all for participating in today's call. Joining me today is Puneet Dhillon, Sky's President and CEO, Chris Twitty, CSO, and Caitlin Arsenault, Sky's CFO. Before we begin, I'd like to caution that comments made during this conference call will contain forward-looking statements under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, including statements about Sky's expectations regarding its development activities, timelines, and milestones. forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially and adversely, and reported results should not be considered as an indication of future performance. These forward-looking statements speak only as of today's date, and the company undertakes no obligation to revise or update any statements made today. I encourage you to review all the company's filings with the Securities and Exchange Commission concerning these and other matters. I'll now turn the call over to Puneet Gillan.

Good afternoon and thank you for joining us. I'm here with members of our management team to review Sky's first quarter 2025 performance. I'll briefly recap our key upcoming clinical milestones and highlight our operational roadmap for the rest of 2025 before turning it over to our CSO and CFO to share more details around our preclinical data and financials. We delivered meaningful scientific, clinical, and operational progress this quarter. Most notably, we completed enrollment in our Phase 2a CBON trial ahead of schedule. We've now moved forward with an amendment to extend the study to 52 weeks. This positions us to collect longer-term data on safety, tolerability, and efficacy, both as monotherapy and in combination with GLP-1. Lastly, we generated compelling new preclinical data that further validates the potential of namazumab as a weight loss therapy. Nemazumab continues to stand out with a differentiated mechanism that is distinct from both peripherally restricted small molecule CB1 inhibitors and GLP-1 agonists. Importantly, our recent preclinical studies demonstrated a truly peripherally restricted antibody like Nemazumab can potentially result in significant weight loss similar to a less restricted small molecule. And Nemazumab has the potential to provide additive weight loss to an incretin memetic like trisepatides. Later, our CSO, Dr. Chris Twitty, will discuss this new data in more detail. These findings reinforce our belief that namazumab has the potential to deliver durable weight loss with fewer safety concerns. We'll present additional data, including mechanistic and combination findings, at key scientific and investor events this year, starting with ECHO next week and ADA in June. Clinically, we are on track. Patients continue to receive treatment The Data Safety Monitoring Committee has completed three reviews with no safety concerns. That engagement remains high. Based on this progress, we expect to report top line weight loss data for the 26-week primary analysis of CBEYOND in late Q3 or early Q4. Before I pass it on, I want to address one topic proactively, the evolving policy environment. While our focus remains on disciplined execution, we're operating in a period of regulatory uncertainty marked by potential shifts in drug pricing policy and a lack of clear direction from federal healthcare leadership. Ongoing transitions at the FDA and NIH raise important questions about how innovation will be balanced with regulatory oversight in the years ahead. At Sky, we've assessed our exposure and believe it's limited in the near term as we prioritize our clinical development milestones. We're on track and we're tracking developments carefully. and we have preserved flexibility in our supply chain and capital deployment planning. Kate will speak more to how we've accounted for these variables in our financial outlook. Overall, we feel that we're in a solid position to move forward with the next stages of the Massimabs development lifecycle, and that we're uniquely positioned to help address the chronic nature of obesity and the need for sustainable long-term solutions. Chris, over to you.

Thank you, Penny. I'm pleased to share our thoughts on a few recent preclinical studies with the MathMath, a novel antibody-based, peripherally-restricted CB1 inhibitor. These studies were designed to not only address the hypothesis that a truly peripherally-restricted CB1 inhibitor, such as the MathMath, can effectively drive weight loss, but to also generate mechanistic data to support Scott's differentiated approach to CB1 inhibition. Recent biomarker analyses from our initial mouse DIO study has further extended the impact of the dose-dependent weight loss observed with the Mathemap treatment. Specifically, now we can report the Mathemap-dependent reduction in fasting insulin levels that complement significant glycemic control as well as productive modulation of key appetite-regulating hormones, including GLP-1 and leptin. Additional datasets also highlight significant reduction of inflammation in adipose tissue as well as liver steatosis. We are also happy to report that this initial study has now been repeated by an independent lab with very reproducible results, not only in terms of the magnitude of weight loss and body composition, that is preservation of lean mass with significant reduction of fat mass, but also with positive changes in glycemic control. This repeat study also looked carefully at food consumption and noted a significant reduction in cumulative caloric intake, slightly less but in line with semaglutide. Collectively, these studies highlight that namazumab-dependent efficacy is driven by multiple peripheral pathways coordinated through different organ systems. Building on our monotherapy studies, we compared namazumab, monluniband, a small molecule CB1 inhibitor, and the dual GLP-1 GIP agonist, terzepatide, both alone and in combination with namazumab, using our DIO model. We chose to use higher yet clinically translatable doses of CB1 inhibitors with the masinab having a similar level of exposure as the current phase 2 dose and monolunumab being slightly higher than its 20-day daily phase 2 dose. Those CD1 inhibitors demonstrated significant weight loss, over 23%, driven by reduced fat mass with lean mass preservation. We are encouraged that skies highly restricted in the masinab drove similar efficacy compared to the less peripherally restricted CD1 inhibitor monolunumab in a DIO model at clinically relevant doses. This study further highlighted that while an active yet suboptimal dose of transeptotide could yield a similar level of weight loss as namazumab, the combination with namazumab produced 31.5% weight loss. These results combined with our mechanistic data strongly support the potential for namazumab to be effective as both a monotherapy and as part of a combination approach to address the growing obesity epidemic. These in vivo studies continue to support our belief that our differentiated antibody approach can provide meaningful efficacy without the challenge that current small molecule inhibitors face, which is brain exposure that can cause unwanted neuropsychiatric side effects. To address this potential advantage, we ran a series of in vitro potency experiments designed to leverage a critical mechanistic difference between anathema and small molecule inhibitors. Unlike small-molecule CB1 inhibitors such as monoludivant that bind to the CB1 receptor at the orthosteric site, that is, the same site as the endogenous agonist, primarily the endocannabinoids AEA and 2-AG, the mass amount binds at the allosteric site and inhibits CB1 in a noncompetitive manner. We modeled a low concentration of CB1 agonist at 50 nanomolar, representing potential physiological conditions, where both drugs showed similar potency. However, when challenged with an elevated concentration at 2,000 nanomolars, mimicking a pathological state such as obesity, in which endocannabinoids become up-regulated, the mass amount potency remained remarkably stable while monolute events activity was significantly compromised. This differentiated mechanism has significant clinical implications. In obesity, where endocannabinoids can be greatly up-regulated, Small molecule CB1 inhibitors such as monolidibat may face increasing competition to bind to the receptor. This circumstance may potentially require higher doses of the small molecule inhibitor, which will increase brain exposure and the potential for neuropsychiatric risks. Conversely, nemacimab's allosteric binding avoids this competition, maintaining relatively similar potency regardless of endocannabinoid concentration. These data suggest that namazumab may offer the widest possible therapeutic window among CB1 inhibitors, potentially delivering significant metabolic benefits without having to navigate around the hurdle of neuropsychiatric side effects associated with achieving an appropriate peripheral exposure. We look forward to continuing our preclinical research efforts focused on further characterizing namazumab's differentiated and clinically relevant mechanism of action and having more data to share over the next month. Now, I'll turn the call over to our Chief Financial Officer, Caitlin Arsenault.

Thanks, Chris. After the market closed today, we issued a press release and filed SCEI's Form 10-Q with the Securities and Exchange Commission outlining our quarterly financial results. We encourage you to reference the filing for details of our financials and the risk factors described in our other filings with the SEC. I will now provide a brief overview of key financial results for the first quarter ended March 31st, 2025. Cash and cash equivalents and short-term investments totaled $59.2 million as of March 31st, 2025. Our cash flow guidance remains intact with the expectation that our current capital will fund operations and key clinical milestones through at least Q1, 2027. allowing us to achieve completion of the Phase IIa study for namathamab and Phase IIb manufacturing activities in anticipation of our future dose-ranging study. Research and development expenses for the three-month-ended March 31, 2025 were $7.2 million as compared to $1.9 million for the same period in 2024. The increase was primarily due to contract manufacturing and clinical trial costs associated with our Phase IIa clinical study for namathamab. salaries and stock-based compensation, consulting and depreciation expense. Our general and administrative expenses for the three months ended March 31st, 2025 were 4.6 million as compared to 4.2 million for the same period in 2024. The increase was primarily related to investor relations, marketing and communication costs and consulting and advisory fees. Our net loss for the three months ended March 31st, 2025 totaled 11.1 million with non-cash share-based compensation expense of $2.2 million, compared to $5 million for the same period in 2024 with non-cash share-based compensation expense of $2.5 million. In closing, I'd like to briefly address how we view the uncertainty and implications of the proposed tariffs by the current U.S. administration and any potential impact we anticipate as it relates to our manufacturing activities. Our drug substance is currently being manufactured in Germany with no expected impact from tariffs on raw materials or excipients, as they are shipped directly to our European partner from sources outside the U.S. Our final drug substance is shipped to the U.S. and is currently unaffected due to its classification under the applicable customs code. Our final drug product is finished in the U.S., and we currently foresee no significant impact on this stage of the supply chain, though we are closely monitoring developments. We anticipate that tariff pressures will affect pharmaceutical products that are manufactured and finished outside of the U.S. and sold into the U.S. market, but that U.S.-based manufacturing could also face increased costs due to imported raw materials from other regions. We are actively tracking these changes and engaging with multiple global manufacturing partners domestically and abroad to maintain an agile, long-term strategy. Our goal is to de-risk future supply planning as the CBOM program advances. This concludes our prepared comments for today. Thank you very much for joining us and we'll now open the call for questions from our Covering Cell Site Analyst. Operator, over to you.

Thank you. The floor is now open for questions. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star 1 again. If you're called upon to ask a question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your questions. One moment for your first question. Your first question comes from the line of George Farmer of Scotiabank. Your line is open.

Hi, this is Chloe on for George. Thank you for taking our questions. A couple from us. So number one, in terms of preclinical data, what can we expect to see at ADA? And I believe you mentioned ECO next week, so a little more detail around that would be helpful. Number two, so on monomunivant, so we know that – well, NOVA has said that they are planning on presenting their full phase two aid data this year. So last September, when they had the data, so that had pretty bad negative recruit to, to your stock, do you think by now, now that you have, you know, this, this, uh, preclinical data out public domain, I think by now investors have kind of begun to grasp the difference between the massive mob and these and, and mongrel advance. And do you think this time around the reaction will be more muted? It's not positive. on your stock, and I'll have a follow-up after that.

Hey, Chloe. This is Puneet here. I'm going to defer the ADA versus the ETO presentation and what to expect there to Chris, because him and his team have been working really hard on that data package. But I appreciate the little bit of a layup on the other question regarding Monlunabat and the full data set. Yeah, we were carefully paying attention to what guidance Novo's been giving regarding that. And on the same note, I think what's been very important to us as a management team and overall in terms of differentiation is being very clear in terms of our mechanism. And we've, as you've seen multiple times, we've really tried to differentiate ourselves from the small molecule space. We've now demonstrated numasmab's weight loss efficacy in these preclinical models, and it's not only comparable to molnumab, but it's also shown additive effect to triseptide in combination, and that's the last data set that was just publicly made available where we achieved over 30% weight loss in DIO models. So I think... We, you know, it's just hard to predict at this point. We do think that the street is better equipped with that background. We've been receiving, sorry, we've been received well from the information that we've laid out, even received well from our counterparts, because we've had a chance to have dialogue there as well. That combination potential is also, I think, really evident in terms of now with preclinical data, and everyone wants to see that read-through with our clinical data with the semaglutide combo. So I hope that your prediction is right, and there's going to be a better kind of separation from that. But that is why the rest of the work that we're doing on the preclinical side continues to be very data intensive, and we're making an effort to be at these scientific conferences. So I'll turn it over to Chris, and he can tell you expectations on that side.

Thanks, Dene. Regarding ECO, we've developed and sort of put together a pretty cohesive model based on published clinical data that looks at the peripheral versus the central activity of different CB1 inhibitors. And it overlays our own Phase II dose, really looking at this from the lens of PK and PD activity. And so, we went into some depths and really focused on really presenting that model. So, You can look forward to that at ECO and, you know, not to give away the punchline, there's actually a lot of interesting pieces that come out of this work, but ultimately I think it makes a really convincing case for the necessity for peripheral CB1 inhibition and speaks to the central, the brain activity that unfortunately is a hurdle that the small molecules are contending with. it really presents that as driving the neuropsychiatric AE. So a bunch of strong data that helps really bring that to focus. And so that'll be the driver there at ECO. In terms of ADA, we'll be showing more in-depth and additional preclinical data. So we have a bunch of very interesting biomarker data, some of which came out in a press release and is up on our current deck you can find online. There's more of that, so really looking at mechanistic data that helps really support this concept of coordinated organ systems driving peripheral mechanisms that allow weight loss to occur, not just from anorexigenic drivers, but really a few different pathways. We think it's quite compelling. In addition to that, in our initial DIO setting, we have combination data, which will also be highlighted there, along with some very interesting biomarker data in support of that. So that'll be the thrust of ADA. And I think we mentioned this last time, we have now multiple colonies with multiple collaborators and labs running in parallel. So our cadence of research is just increasing. There's a lot of interesting questions and data sets on the horizon. We'll look forward to sharing that beyond ADA.

Great, thank you. Super helpful. If I may squeeze in one last question, this is regarding regulatory interactions. So you've talked about what you see in the mass setting into this obesity treatment paradigm, right? Across different populations, exposed refractory or non-responders to credence, for instance, So have you had these conversations with FDA yet or plan to? And just walk us through your plan there.

Yeah, that's a great question. So I can kick it off. And I know Dr. Arora is on the line. I see him on the portal. So I'm going to let him talk about the regulatory interactions. But there's been two kind of key pavities, Chloe, that's important for us. One is being very clear, crystal clear, in terms of what's our roadmap for approval. And the approval regulatory development strategy in obesity or anti-obesity medications hasn't shifted. So even with the new guidance, we're sticking to that overall strategy in terms of obtaining approval as a monotherapy. But the big but there is that there's a... obviously an advancing kind of landscape with the increment class continuing to demonstrate success. But at the same time, there's there's this opportunity of patients coming off drugs, discontinuation rates, tolerability issues, maintenance opportunities, and there lies a significant opportunity. So what one activity that we've been really active in is active in not active in as a target, but is the is the discussion with KOLs and how that defines the target product profile and how that refined target product profile goes after a very clear market. And we probably have some of that information become available later in Q2. And then the second strategy is the regulatory strategy, which a lot of it gets defined after the data readout on the 2A, but it's Dr. Arora wants to elaborate. I'm going to turn it over to him.

Yeah, sure. Thank you. Chloe, in the not-so-distant future, I'd say in the near future, we are going to have an opportunity to have these regulatory interactions. As Puneet pointed out, we're going to have data from the Phase IIa, which will be available in Q4 this year, and we're going to take that data and take that opportunity to have discussions with the FDA and possibly with other regulatory Our priority is both in terms of seeking their advice and also proposing a definitive dose ranging phase to be studied. And that will be an opportunity for us also to discuss population so we can study and how we can define them. So I think that with data and.

Sorry, I can tell you that was cut off, but thanks again for taking my questions. This was really great. Thank you.

Your next question comes from the line of Jay Olson of Oppenheimer. Your line is open.

Oh, hey, thanks for providing this update. Can you please remind us about your findings from the DIO model on body composition and how namazumab may help preserve lean muscle mass in combination with GLP-1 And then I guess looking ahead longer term, just how are you thinking about the magnitude of the commercial opportunity for namazumab in combination with GLP-1 versus namazumab monotherapy? And then I had to follow up if I could, please.

Hey there, Jay. I'm acting as operator right now, so I'm going to let the... Chris, take that first question, and then maybe that's teed up really well for two who's been handling all the commercial assessments. So after Chris, two can give you a response in the second part of your question.

Thanks, Puneet, and thanks for the question, Jay. So we actually, just to clarify, the combination data was around trisepatide, so in combination and alone with trisepatide. So in terms of body composition, we did see When we look at namazumab monotherapy, similar to what we saw in the previous repeated studies, which, by the way, I just note those were done with independent labs and we see very reproducible data, we see body composition where significant reduction in fat mass with preservation of lean mass. And we see that to a lesser extent with triseptide. Triseptide alone still significant, but it's trending up toward less fat mass. And in combination with namazumab, we see the greatest amount of reduction. They're all fairly, you know, notable. So there's not like a huge shift, but we do see that, in fact, in combination, it looks like there's even more fat mass there. So it really sets the stage for combination. If we look at the weight loss, we see this nice additive effect, partially additive effect, And this again gets back to some of the mechanism where there is some overlap in the in the anorexia genetic driver compartment, if you will. So the cork intake both can impact that pathway, but there's additional pathways that CD1 inhibition with the mass and that touch on and we feel that's where we get this additive nature of weight loss. And two, do you want to take the next piece?

Yeah, happy to, but Jay, would you mind just repeating your question?

Oh, yeah, just how you're thinking about the relative magnitudes of the commercial opportunity for the combination of namazumab plus GLP-1 GIP versus the magnitude of the opportunity for namazumab monotherapy.

Yeah, we've been – thanks for that question, Jay. We've been modeling sort of our commercial opportunity. As Penny said, we've been doing a lot of – sort of a commercial assessment of the massimab in terms of what the target populations really are. And as Puneet highlighted, we think we do have that opportunity both as a monotherapy and in combination monotherapy, most likely in the area where patients are intolerable or unresponsive or have a contraindication to GLP-1s, which we think is probably a much larger opportunity that some people may have originally thought. In terms of the combination opportunity, again, I think this is a potentially large opportunity where you have a class of patients who do require some significant weight loss. Again, looking at that 20, 25% plus weight loss, likely in that class three obese population. where maybe, again, they're not tolerable to the higher doses of, let's say, a triseptide and can't achieve those higher weight losses, or they need just additional weight loss on top of the triseptide or other GLP-1 class. When we look at sort of what those commercial opportunities are between the monotherapy and combo, You know, they're relatively equal, I think, at least at this point in terms of how we're seeing the market. They both are quite large in the, you know, billion dollar size markets. And, you know, one hasn't necessarily differentiated itself, at least at this point, as we've been going through the analysis.

Okay, great. Thank you. That's super helpful. And if I could squeeze in one last follow-on question. Have you guys done any work on the co-formulation of namazumab with GLP-1 or GLP-1 GIP, and is a fixed-dose combination technically feasible, and can you comment on any potential IP advantages or lifecycle management advantages of doing a fixed-dose combination?

Dr. Timothy Stenzelman Yeah, that's a great question there, Jay. The opportunity for us in terms of co-formulation obviously exists, but that hasn't been something that we've explored yet. The first proof of concept is going to be just in terms of the dosing happening at the same time in the current trial. Instead, there has been interest from a fixed dose perspective. We definitely see an advantage of being a biologic, being an antibody, that there's really a future where you can be a CB1 plus story. So stay tuned. You know, I think first things first is we want to demonstrate namazumab's advantage as a monotherapy and highlight this data. And it's been well supported by the preclinical evidence. And we expect that later this year, once we get through the clinical data, we can start highlighting what does that pipeline look like as a CB1 plus story that includes fixed dose.

Okay, great. Thank you so much for taking all the questions.

Your next question comes from the line of Albert Lo of Craig Hallam. Your line is open.

Hi, guys. Thanks for taking my questions. Maybe the first one, I saw that there's some safety reviews that have not raised any concerns. I was just wondering, If there are any other reviews planned, and would any severe or serious neuropsychiatric AEs be raised in these reports? Thanks.

Dr. Arora, you want to take that question? Sure. So we are actually holding these unblinded reviews on a quarterly basis. So the independent DMC meets every quarter, and they are provided with uh unblinded data uh for on on safety uh in order to review now what we what we have told you and as you were mentioning was that they've reviewed that data and told us that there were no concerns Moving forward with the study, they are provided with a list of all the adverse events that are reported in the study and the serious adverse events. We also report any neuropsychiatric events that may occur in the study as adverse events of special interest. So those are also channeled into the DMC. So they get to review all of this, and they are doing it on a quarterly basis, and no concerns have been raised so far. The next review is scheduled for July the 18th, and they will be ongoing from there on until the study ends.

Okay. So it sounds like the review board has some, I guess, discretion over, I guess, what weren't a concern. Is that right?

Yes, I mean, they get all of the data that's available for the study, and we have on that review board two psychiatrists, actually, and we have people who have experience both with CB1 and with obesity studies in general. So, you know, it's a very experienced set of people who understand exactly how these studies run, what this data looks like, and what they're looking for.

Okay, thanks. Maybe one follow-up question. I just wanted to be sure I still kind of understand what's the expectations for what would be a strong separation from placebo and monotherapy at 26 weeks. Would this still be 8%?

Yeah, Albert, that's an excellent question. So the primary endpoint is for 8%. At 26 weeks, you know, based on what has been kind of shared. Now, when we put that number out, we didn't have the benefit of 16-week data from Monlunabant, which showed 5.7% placebo-adjusted if I recall. So for us, we are expecting to see separation between placebo and active, and obviously we're targeting over 5%. The study has a design based on 8%.

Okay. All right. Thank you. And if I can just squeeze in one last one with this follow-up here, or start with this. Are you still playing that? Sorry. I can see with this open label extension for the 26 weeks, It looks like there may be some gaps in the treatment period. I was just wondering, I guess, if you have plans on how to interpret this data to, I guess, account for some variations here and potential weight changes during these gaps.

Yeah, there is a rollover period that we've had to account for because, naturally, there's an operational kind of updates that come along with adding an extension that wasn't previously part of the protocol. But we don't, I mean, the data will be collected based on weight and other parameters at the start of the extension as well. So it's, you know, we don't know if there's going to be variability, but if there is variability, it'll be collected in terms of the data, and we can discuss that once we have all that information.

Thank you.

Your next question comes from the line of Ted Tenthoff of Piper Sandler. Your line is open.

Great. Thank you very much, and thanks for the update. I wanted to get a sense. I know you guys extended the CBN study phase two to 52 weeks. What is the incremental benefit from going from 26 weeks to 52 weeks, considering you still have the primary EFFICACENCY READOUT AT 26 WEEKS. AND THEN HOW DOES THIS IMPACT POTENTIAL TIMING FOR A PHASE 2B START? WOULD YOU HAVE TO WAIT FOR THE FULL 52-WEEK DATASET FOR CBEYOND? AND JUST WANTED TO GET A SENSE FOR HOW YOU'RE THINKING ABOUT THAT.

THANK YOU. THANKS. Pretty important, pretty important question. Like as we as we talked about in the last earnings call, what we really wanted to try to do is maximize what we could from from the current trial. So having one having the trial up phase two way up and running with the primary endpoint based on 26 weeks, it did allow us the flexibility to leverage a study that's already there. Patients already enrolled. and then generate another data point that allows us to have broader efficacy safety data um you know other other information that we're collecting from the from the trial um so that that that's been one of the key factors and and it's always been important for us to eliminate any white space between any of our development objectives so at the moment this Extension actually slots in really well before the phase 2B starts and allows us to take the phase 2A data, able to have a productive discussion with the agency about what a phase 2B would look like, and at the same time continue collecting information based on this extension before that phase 2B begins, and perhaps even inform the phase 2B to some extent. But at the moment, it hasn't created any extra time. In fact, it's slotted really well operationally, and we have the drug product to be able to get that additional data point. The last thing I would say is that the 52-week data point is another important thing to continue to build confidence on the broader safety that we want to see with this mechanism. So I think... That's been another important factor, as well as the tolerability information. Dr. Arora, do you want to expand on anything I missed?

Yeah, I think you covered a lot of it. I just want to add a couple of small things. So in the monotherapy arm, because it's an open-label arm, we are able to continue to refine our PK-PD models as the study goes on beyond 26 weeks, and that will help us in picking the correct dose range for the Phase IIb study. So that data will be helpful. And of course, as Puneet pointed out, the safety data is invaluable because we are treating longer and being able to show that the MS-VIB is safe and tolerable. There is also a second arm to this study. So we're also extending the combination dose. And the combination dose isn't currently being tested in the proposed phase 2B, which will be a dose ranging for the monotherapy. So for the combination dose, we're getting this additional 52-week data, which just adds to what happens when you dose these drugs together and what happens to the curves and the trajectories of weight loss. So we think that data will be really useful both for safety and for efficacy.

Gotcha. So you think the phase 2B would have to be a monotherapy study, or could there be combo arms?

Well, at the moment, the phase 2B is planned and proposed as a monotherapy study, because what we need to do is to do a proper dose ranging, right? We need to understand what the optimal dose for namasmab is. It doesn't preclude the idea that we could do a study with the combination or do other work, but it is necessary to find that optimal dose in order to go to phase 3.

Yeah, perfect. Thanks, guys.

Your next question comes from the line of Kristen Kluska of Cantor Fitzgerald. Your line is open.

Hi, everyone. Based on some of these preclinical studies that you've conducted, the ones that are ongoing, I'm wondering if this has changed the way you're thinking about how the trial is powered. So, you know, perhaps are you walking away with greater conviction in the percents that you've provided us with, or essentially if any of your parameters or thought processes changed. And outside of just the monotherapy, same thing with the combination. Thank you.

Yeah, Kristen, that's a really great and important question that you've raised. The data generated so far preclinically uh wasn't something that we that we had uh you know when when we launched the program so this demonstrating that we've now i think there's three important kind of important takeaways here that we've demonstrated this robust in inhibition of cb1 across multiple assays data information is available in the deck and that shows um you know the potency relative to or the the differentiation relative to small molecules We've continued to benefit from a really strong safety profile, right? We had this previous work of multiple distribution studies done in NHPs that didn't show any CNS penetration. We've achieved now monotherapy of like 16 to 23.5% weight loss in several studies and repeat studies as monotherapy and now shown over 30% in a combo model. Across the board, it checks a lot of boxes. How does that translate to humans? Of course, it gives you this aspect of, well, we feel more confident around the mechanism, and there's this component that comes along with it that we expected to translate into the clinic. to be at the same time transparent. These are my studies, so we have to put that in one aspect. The only other confident thing that we can leverage is that the DIO models across the landscape have been, interestingly, a very good tool in the therapeutic area across different mechanisms. the DIO models have translated to some degree in the clinical setting. So that's kind of our broad take. Chris, do you want to take any different approach on answering Kristen?

No, I think you touched really all the key points. I might just add a very small detail, and that relates to, and this is sort of the translatability and how well in terms of confidence Do we feel the DIO models will predict what we see in the clinic? And I think you touched on some of the key areas. But one other aspect is, you know, we are dosing. When we look at our DIO dosage, it looks relatively high. And it's worth noting that we have a very different behavior in terms of the BK profile in the mouse than we do in the human. And so we're very mindful of looking at exposures, not necessarily a CMAX. It's really when you understand the whole area of the curve analysis and what the exposure and engagement looks like in these DIO models. And keep in mind that these are obviously very short duration relative to what we're doing in the clinic. So when you look at that all together, you really start to appreciate how we're matching exposure. We're looking at doses that are, you know, we feel very translatable. And, you know, we've seen some success with predicting efficacy in the Ingrident space and arguably looking at the CB1 space with NOBLES dataset, which we feel is actually a pretty significant dataset. This is actually, you know, a very – I think a very strong dataset, and they, too, had DIO data that looked pretty strong. We reproduced that in our own lab. coming back to this idea of translating, we do feel pretty confident that we're going to have an active drug in the clinic. I'll just add that piece, that's all.

Thanks Chris. Thank you.

Your next question comes from line of Andy C. of William Blair. Your line is open.

Okay, thanks for taking our questions. So maybe from the outside world, can you kind of talk us through some of the discussions that you will be having with the FDA in terms of the protocol and then just, you know, what are some steps that you need to have a meeting with the FDA, the kind of logistical part of that. And the second question I have, I just wanted to make sure. So, so, Chris, you mentioned about all the preclinical data that really kind of accentuates the clinical differentiation of the math math. So was that also a part of the April 15 disclosure? I just want to see if there's any overlap, or is there any new data that you disclosed today? Thank you.

Yeah, thanks, Sandy. So we haven't disclosed any new data today. What we expect is updates to these datasets that we've shared recently in upcoming scientific meetings. And we'll keep some of that information close to our vests until we get there. But there will be an update at those meetings. And what we're committed to, as what Chris kind of pointed to earlier, is we now have multiple efforts underway, domestic and international, where we are going to continue to build on the understanding of the mechanism and support our clinical activities and biomarker activities and other stuff. So because of that workflow, that is allowing us a much larger data set to work with and continue to support our clinical activities. I'll turn it over to Dr. Arora and then Chris, you can elaborate on anything after Dr. Rohrer.

Yes, so your question was about regulatory interactions. As you know, with protocol amendments, the NTA doesn't ask for and doesn't grant actual meetings, so we have submitted the protocol amendment to the FDA. They have asked us for some minor clarifications at this point, and we have already sent them the responses for that. It's our expectation that we will be able to sort out the minor issues that have been raised, and we will be able to start rolling patients into our extension. It's very unlikely that they will ask for any kind of actual meeting around the protocol amendment.

Your next question comes from, pardon, your next question comes from the line of John Wolben of Citizens JMP. Your line is open.

Hey, thanks for taking the question. I'm wondering if you guys have looked at blinded baseline data and specifically wondering if you have any concerns like we've seen with some of the anchor teams about reduced efficacy in larger individuals and also in the Hispanic population, if there's anything in the demographics that you know, caught your eye when you take a look at that.

So, Jonathan, we're still blinded to the data, so we don't really have access to anything. But Dr. Arora, do you want to take a stab at anything that you want to provide context from your experience?

Yeah, so, you know, we have, I think we've managed to get a pretty good representative population recruited for this trial. We do have some Hispanic representation and we also have a pretty good weight range to my mind. So once we unblind, we, you know, to the extent that sub-analysis is actually possible based on these parameters, we will be able to do that. But at the moment, as Puneet pointed out, we are blinded. So it's hard to know right now whether or not there's any correlation or whether any of these individual parameters are making a difference.

And how do you think about managing discontinuations in the combination arm? And are you allowing dose adjustments for patients on semaglutide?

And so that's one of the reasons that we've kept the The rollover gap small is that we don't want patients off semaglutide for any extended period. They are limited to being off their drug for only four weeks, and this will only account for the few initial patients who will be able to join the rollover extension. when we are able to begin it and have recently finished. After that, everyone who rolls over will roll over directly. So there will be no gap and we won't need to do any dose adjustments for the semaglutide because they're already on effective doses of semaglutide. For the few patients who will have this small gap, we have made some allowance to be able to go back a little bit on those and be able to, if they're required to, and to be able to readjust to the semaglutide. We know that these people can tolerate the effective dose of semaglutide because they will all have completed 26 weeks of treatment on it.

Got it. All right. Thanks, guys.

With no further questions, ladies and gentlemen, this concludes today's conference call. You may now disconnect.